Mu-Opioid Antagonist Effective for Drug-Induced Constipation

But questions remain about whether the need is currently unmet

PALM SPRINGS, Calif. -- Naldemedine, one of the new class of mu-opioid antagonists, relieved opioid-induced constipation in chronic noncancer pain patients in a phase III trial, a researcher reported here.

At the end of 12 weeks of treatment, 47.6% of the naldemedine group met the drug's primary efficacy endpoint compared to 34.6% of the placebo group, a difference that was statistically significant (P=0.002), reported Juan Camilo Arjona Ferreira, MD, senior vice president for clinical development at manufacturer Shionogi's U.S. division.

But, with no active comparator tested, the trial didn't settle the question of whether the drug fills an unmet need.

The medication differs from standard constipation medicines because it targets mu-opioid antagonists in the gut -- the very receptors affected by opioid medications, Ferreira explained.

"What (naldemedine) does is actually reverse the effect of the opioid. Laxatives in general are not addressing the cause of the problem while this does," he told MedPage Today during his poster presentation at the American Academy of Pain Medicine's annual meeting.

This particular mu-opioid antagonist is in a once-a-day tablet form, while others in development are injectable. They don't cross the blood brain barrier or interfere with opioids treatments.

A total of 547 patients were randomized to receive either 0.2 mg naldemedine (274 patients) or placebo (273 patients) once daily for 12 weeks. Patients' mean age was 53, had chronic noncancer pain, had been taking opioids for 3 months or more, and were not currently using or were willing to discontinue laxatives.

They all had opioid-induced constipation defined as having no more than two bowel movements per week.

The primary efficacy endpoint was having a "positive response week" -- three or more spontaneous bowel movements in a week, and at least one more than at baseline -- for 9 out of the 12 weeks, and in at least 3 of the last 4 weeks of the 12-week period.

"They had to be responding throughout the 12 weeks," Ferreira said.

For responders in the treatment group, the effect was apparent quickly. "Right in the first week patients were having an average of about five bowel movements per week," he said. Once improvement occurred, it was generally sustained through to week 12.

The placebo group had general improvements too, and had an increase up to an average of about three spontaneous bowel movements per week. This occurred after the second week. At this level, they wouldn't have qualified for entry into the study.

"The placebo effect is real, especially in conditions that are driven by symptoms where the mind plays a big role," Ferreira said. Still, the difference between groups was statistically significant.

The most common side effects more frequent in the active-drug group were abdominal pain (17 in the naldemedine group, five in the placebo group); diarrhea (18 naldemedine, eight placebo), and nausea (13 naldemedine, seven placebo). In pain assessments, three participants were considered to have possible opioid withdrawal (two naldemedine, one placebo).

Overall, "we feel that we showed it works well, is well tolerated, and works only peripherally. It's a good option for physicians and patients," he said.

But one physician not connected with the study told MedPage Today that he questioned the need for such a treatment.

"There are a lot of medications that have been around for a while for managing constipation for many years, they tend to be inexpensive, many of them are available over the counter. We know them and understand how to use them," said Erin Krebs, MD, MPH, of the University of Minnesota in Minneapolis.

She said she doesn't feel there is a need for a new option for her patients. Existing products "are pretty good and work for most people."

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